picibanil and Brain-Neoplasms

To elucidate the mechanism of apoptosis in brain tumors, we analyzed the expression of apoptosis-related gene products in cultured glioma cells and biopsied brain tumor specimens. Fas, Bcl-2 family (Bcl-2, Bcl-x and Bax) and ICE family (ICE, Ich-1) were found to be involved in tumorigenesis of certain brain tumors. It was also clarified that OK-432 activated mononuclear cells could kill T98G glioblastoma cells by apoptotic mechanism through the Fas ligand/Fas system.

Topics: Apoptosis; Base Sequence; Brain Neoplasms; fas Receptor; Humans; Immunotherapy, Adoptive; Leukocytes, Mononuclear; Molecular Sequence Data; Picibanil; Proto-Oncogene Proteins; Serpins; Signal Transduction; Tumor Cells, Cultured; Viral Proteins

Topics: Animals; Antibodies, Monoclonal; BCG Vaccine; Brain Neoplasms; Cell Fusion; Glioma; Humans; Hybridomas; Immunotherapy; Interferon Inducers; Interferons; Leukemia; Levamisole; Lymphoma; Mice; Mice, Inbred BALB C; Picibanil

During the period from January 1981 to December 1983, two groups of a total of 51 patients (31 malignant astrocytomas, 17 glioblastomas, and 3 others) were treated with radioimmunochemotherapy using nimustine hydrochloride (ACNU) plus Picibanil (OK-432) (group A) and radiochemotherapy with ACNU only (group B) in a randomized controlled study. Group A consisted of 24 patients and group B of 27 patients. The differences in the background of the two groups were not statistically significant. Survival curves of both groups were shown by the Kaplan-Meier method. The postoperative survival rate at 1 year and 3 years was 70% and 30%, respectively, equal in both groups, and the differences between groups A and B were not statistically significant by the Cox-Mantel test. The side effects seen in group B were most prominent in the bone marrow, and severe leukopenia occurred. However, in group A leukopenia was suppressed after 2 months. Immunologic parameters, such as the purified protein derivative skin reaction test, did not change, but the streptococcus pyogenes Su-strain polysaccharide skin-reaction test became more positive after therapy in group A.

Topics: Adult; Aged; Biological Products; Brain Neoplasms; Clinical Trials as Topic; Combined Modality Therapy; Female; Glioma; Humans; Leukopenia; Male; Middle Aged; Nimustine; Nitrosourea Compounds; Picibanil; Random Allocation; Skin Tests

Topics: Adult; Aged; Antineoplastic Agents; Biological Products; Brain Neoplasms; Combined Modality Therapy; Female; Glioma; Humans; Male; Middle Aged; Nimustine; Nitrosourea Compounds; Picibanil; Random Allocation

Adoptive immunotherapy using OK-432-activated mononuclear cells (OK-MCs) offers cell-mediated and cytokine-mediated pathways for antitumor activity. The effectiveness of direct intratumoral administration of OK-MCs via a catheter/reservoir system was studied in patients with malignant brain tumors. Seventeen patients, 12 with malignant glioma, four with metastatic adenocarcinoma, and one with primary sarcoma of the brain, were treated by OK-MC therapy (1.0 to 11.2 x 10(7) cells/person) between June 1989 and April 1999. The OK-MC therapy was given to patients with tumors progressing despite previous cytoreductive surgery, radiation, or chemotherapy. Adverse effects seen after the therapy were fever in 10 patients, seizure in two patients, and hypotension in one patient. Evaluation by computed tomography or magnetic resonance imaging revealed that seven patients showed no change including three with minor response, and 10 showed progressive disease. Adoptive immunotherapy using OK-MC was safe and well tolerated, but the therapeutic potential is limited.

Topics: Adenocarcinoma; Adult; Aged; Brain Neoplasms; Combined Modality Therapy; Female; Glioma; Humans; Immunotherapy, Adoptive; Male; Middle Aged; Monocytes; Picibanil; Sarcoma; Treatment Outcome

We studied the effect of a streptococcal preparation, OK-432, on the cytotoxicity and the proliferation of lymphokine-activated killer (LAK) cells for use in adoptive immunotherapy. Peripheral blood mononuclear cells (PBMC) were derived from healthy donors and patients with malignant brain tumors. We divided PBMC into two groups; these cells then were stimulated with interleukin-2 in the presence or absence of OK-432. OK-432 was added only in the initial 3 days during the 3-week midterm culture period. Then, we compared OK-432-stimulated LAK (OK-LAK) cells with standard LAK (sLAK) cells in terms of their rate of proliferation and cytotoxicity. OK-LAK cells proliferated more rapidly than sLAK cells. The cytotoxicity of OK-LAK cells increased, whereas that of sLAK cells decreased. We also investigated the phenotypic differences between these two types of LAK cells and found that, on day 21, the OK-LAK cells consisted mostly of CD3-CD56+ NK cells, whereas the sLAK cells consisted mostly of CD3+CD56- T cells. The difference in their level of cytotoxic potential might be explained by the difference of predominant phenotype.

Topics: Antigens, CD; Antineoplastic Agents; Brain Neoplasms; Cell Division; Cytotoxicity, Immunologic; Dose-Response Relationship, Drug; Flow Cytometry; Humans; Immunotherapy, Adoptive; Interleukin-2; Killer Cells, Lymphokine-Activated; Leukocytes, Mononuclear; Lymphocyte Activation; Phenotype; Picibanil; Receptors, Interleukin-2

We have been applying an adoptive immunotherapy protocol to patients with malignant brain tumors using OK-432-activated peripheral blood mononuclear cells (OK-MCs). In order to elucidate the mechanism of OK-MCs' cytotoxicity, we examined the expression of Fas ligand mRNA in OK-MCs and the cytocidal activity of these cells against a human glioma cell line, T98G which expresses a high level of Fas. The expression of Fas ligand mRNA was low in non-treated peripheral blood mononuclear cells and was elevated by treatment with OK-432, irrespective of the dose employed. Apoptosis of T98G cells induced by OK-MCs was unequivocally inhibited by the pretreatment of T98 G cells with ZB4 monoclonal antibody, which binds to Fas and blocks the binding of Fas ligand to Fas. These data indicate that the cytotoxic activity of OK-MCs via apoptosis seems to be at least partly mediated by the Fas ligand/Fas system. Adoptive immunotherapy using the Fas ligand/Fas system could be a new treatment modality for human malignant brain tumors.

Topics: Adjuvants, Immunologic; Adult; Antibodies, Monoclonal; Apoptosis; Brain Neoplasms; DNA Damage; Fas Ligand Protein; fas Receptor; Glioma; Humans; Immunotherapy, Adoptive; Leukocytes, Mononuclear; Membrane Glycoproteins; Picibanil; RNA, Messenger; Tumor Cells, Cultured

We have employed IAR therapy [combination of postirradiation, chemotherapy and interferon (IFN)] for malignant glioma patients. Changes of lymphocyte fractions in patients were evaluated before and after IAR therapy, using a recently developed two-color analysis. Eight malignant glioma patients received irradiation, chemotherapy (ACNU) and immunotherapy (OK-432 and IFN-beta). Peripheral blood lymphocytes taken during hospitalization with IAR therapy (first half and latter half), and every 3 to 6 months for 2 years at the longest after IAR therapy were double-stained with FITC- and PI-labelled antibodies and two-color analysis was conducted by a FACS Analyzer. Six patients out of 8 survived for 6 months to 2 years, 2 died after 3 and 6 months, respectively. Leu-2a (suppressor/cytotoxic T), especially Leu-2a+ 15- (cytotoxic T) showed a high value. Leu-2a level decreased during treatment, and both Leu-2a+ 15- and Leu-2a+ 15+ (suppressor T) values decreased. Two thirds of the patients showing an increased Leu-2a+ 15+ level died. Leu 3a (helper/inducer T), especially Leu-3a+ 8+ (inducer T) level decreased, but Leu-3a+ 8- (helper T) level increased during treatment. The level decreased in the worse patients. Leu-3a/Leu-2a ratio was low, but it increased during treatment as compared with the results of conventional therapy. Leu-7, Leu-11a, NK activity, and gamma-IFN productivity were further studied. Treatment combined with IFN revealed an influence on the T cells resulting in an increase of helper T level and suppression of suppressor T level.

Topics: Adult; Aged; Brain Neoplasms; Combined Modality Therapy; Female; Glioma; Humans; Interferons; Male; Middle Aged; Nimustine; Picibanil; Radiotherapy Dosage; T-Lymphocyte Subsets; T-Lymphocytes, Cytotoxic; T-Lymphocytes, Helper-Inducer; T-Lymphocytes, Regulatory

In this study, we tried to examine the efficacy of a cytotoxic factor which is induced by periodic, repeated local administration of OK-432 into the tumor cavity of malignant glioma patients. OK-432 was administered intratumorally via a tube to 4 malignant glioma patients on Days 1, 3, 5, 7 and 12 in doses of 0.5 KE, 1 KE, 2 KE, and 3 KE, respectively. Cerebrospinal fluid (CSF) was collected several times during the 24-hour period beginning immediately after the administration on Day 12. The CSF was added to the culture medium of rat glioma cells (GA-1 and C-6) in order to observe the cytotoxic effect morphologically. The clinical efficacy in the patients was evaluated from the changes in tumor size observed by CT. CSF collected from the tumor cavity of 3 patients was bloody. By adding this bloody CSF, a significant morphological cytotoxic effect was observed on both the GA-1 and C-6 glioma cells in culture. The level of cytotoxicity was higher with the bloody fluid collected at 4 to 24 hours after the final administration than with the bloody fluid collected immediately after the final administration. The cytotoxic effect of this fluid was stronger than that of rabbit TNF (tumor necrosis factor) serum induced with P. acnes and LPS.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Brain Neoplasms; Glioma; Humans; Injections, Intralesional; Picibanil; Rabbits; Rats

To ascertain whether tumor-specific immune response occurs in patients with malignant brain tumors, lymphocyte blastogenetic responses to tumor cells were examined in 18 patients prior to operation and other treatment. Among 12 patients with malignant glioma, the peripheral blood lymphocytes (PBL's) showed a positive blastogenetic response to their own glioma cells in seven (58.3%), whereas the tumor-infiltrating lymphocytes (TIL's) showed a positive response in only three (25%). In four (66.7%) of six patients with metastatic brain tumors, however, both the PBL's and TIL's showed a positive blastogenetic response to their own tumor cells. In these four patients, this lymphocyte blastogenetic response to tumor cells were at a much lower level compared with phytohemagglutinin P or allogeneic lymphocyte stimulation. Furthermore, these responses were increased when the cells were cultured with interferon-gamma (500 U). Other lymphokines had no effect on the response. This method appears to be useful in identifying the tumor-specific immune response in patients with malignant brain tumor.

Topics: Adolescent; Adult; Aged; Antibody Formation; Brain Neoplasms; Glioma; Humans; Interferon-gamma; Interleukin-2; Lymphocyte Culture Test, Mixed; Lymphocytes; Middle Aged; Picibanil

In considering immunological approaches to treatment of the patients with malignant brain tumors, it seems very important to enhance the tumor specific immunity. Then, to ascertain whether tumor specific immune response occurs in these patients with malignant brain tumors, lymphocyte blastogenetic responses to tumor cells were examined in 18 patients with malignant brain tumors. Furthermore, to compare the systemic immunological responses with the local responses in the brain tumor tissues, both peripheral blood lymphocyte (PBL) and tumor infiltrating lymphocyte (TIL) were used as blastogenetic stimulators to the tumor cells. The PBL from the patients with malignant gliomas showed any positive blastogenetic response to their own glioma cells in 7 or 12 cases (about 58%). But, TIL from these patients showed a positive response in the only 3 cases (25%). In 6 cases of metastatic brain tumors, otherwise, their PBL showed any positive blastogenetic response to their own tumor cells in 4 of 6 cases (about 67%), and their TIL showed any positive blastogenetic responses in these same 4 cases. So, the tumor specific immunological responses may be stronger in the patient with metastatic brain tumors than in the patient with malignant gliomas. These immunological responses were, furthermore, more weak in the brain tumor tissues than in the systemic immunity. Then, this lymphocyte blastogenetic response to tumor cells were compared with other lymphocyte stimulating examination such as rectine or allogenetic lymphocyte stimulation. Our studies revealed that this lymphocyte blastogenetic response to tumor cells were at lower level compared with rectine such as PHA, PWM, and Con A, or allogenetic lymphocyte stimulation.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Brain Neoplasms; Female; Glioma; Humans; Interferon-gamma; Interleukin-2; Lymphocyte Activation; Lymphocyte Culture Test, Mixed; Male; Middle Aged; Picibanil; Tumor Cells, Cultured

A case of synchronous multiple primary neoplasms, an intracranial malignant lymphoma and a gastric carcinoma, is presented. A 63-year-old man was admitted to our hospital with complaints of dizziness and a floating sensation on gait. A CT scan after admission, revealed a well-defined, nodular high density area in the left frontal lobe, which was markedly enhanced by the contrast medium. In order to rule out a metastatic brain tumor, examinations were performed as a consequence, and, the gastric carcinoma was found. A partial removal of the brain tumor and a gastrectomy were performed in two stages. Pathologically, the diagnosis of the brain tumor indicated a malignant lymphoma of large cell type, and that of the gastric carcinoma was an adenocarcinoma. The patient received postoperative irradiation and chemotherapy and was discharged in a good condition. He died of pneumonia 21 months after the operation. Necropsy revealed a marked atrophy of the brain without recurrence of the malignant lymphoma and no recurrence of a gastric cancer.

Topics: Adenocarcinoma; Aged; Brain Neoplasms; Combined Modality Therapy; Gastrectomy; Humans; Lymph Node Excision; Lymphoma; Male; Neoplasms, Multiple Primary; Picibanil; Stomach Neoplasms

Topics: Antineoplastic Combined Chemotherapy Protocols; Astrocytoma; Biological Products; Brain Neoplasms; Combined Modality Therapy; Female; Fluorouracil; Glioblastoma; Humans; Male; Nimustine; Nitrosourea Compounds; Picibanil

Topics: Animals; Astrocytoma; Biological Products; Brain Neoplasms; Cobalt Radioisotopes; Combined Modality Therapy; Glioma; Humans; Nimustine; Nitrosourea Compounds; Picibanil; Rats

Topics: Brain Neoplasms; Glioma; Humans; Interferon-gamma; Interleukin-2; Picibanil

T cells bearing IgG Fc receptors (Tr cells) were determined in 40 cases of brain tumor using the double rosette method, and compared with the changes of PHA reaction, immunoglobulin (IgG A M), performance status, and mass effect on CT in 20 pre-and post-operative and/or radio-clinico-immunotherapeutic patients. The proportion of control Tr cells was 8-19% in 20 healthy adults. Values of Tr cells over 20% were correlated with a poor grade of performance status, and large mass effects on CT. Post-therapeutic change in the value was well correlated with change in performance status, mass effects, and IgG. Our results suggest a correlation between the value of Tr cells and clinico-radiological findings. Immunological analysis of Tr cells serves as a parameter of tumor expansion or prognosis, and could be of significant importance clinically.

Topics: Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Dysgerminoma; Humans; Immunoglobulin A; Immunoglobulin Fc Fragments; Immunoglobulin Fragments; Immunoglobulin M; Lymphocyte Activation; Nimustine; Nitrosourea Compounds; Phytohemagglutinins; Picibanil; Receptors, IgG; Receptors, Immunologic; T-Lymphocytes

Topics: Adult; Aged; Animals; BCG Vaccine; Biological Products; Brain Neoplasms; Female; Glioma; Humans; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C3H; Middle Aged; Picibanil

Chemotherapy was applied for experimental subarachnoid dissemination model of brain tumor which was established in male Wister-SPF (SLC) rats inoculated intracisternally with 2 X 10(5) C6 rat glioma cells. Nontreated animals died about 24 days after inoculation. Autopsy findings of the animals showed localized or multifocal invasion of the tumor on leptomeninges in cisterna magna, and partially infiltration into the parenchyma of the cerebellum and medulla oblongata. Three days after inoculation, the tumor deposition and proliferation already occurred. Several tumor cell layers were found in the subarachnoid space over the cerebellomedullary surface. Tumor bearing animals were at first treated by single agent. These are ACNU administered intraperitoneally, methotrexate administered intracisternally, and OK-432 administered intraperitoneally. In the next stage, combination of these drugs was applied. ACNU, 3 mg/kg i. p., on Day 3, was effective in elongation of median survival time by 23.6%, statistically significant (P less than 0.02). Methotrexate, 0.25 mg/kg i.th., on Day 3, was also effective in elongation of median survival time by 8.4%, statistically significant (P less than 0.05). OK-432, 0.1 KE/kg i. p., daily, 14 times, from Day 3 to Day 16, was ineffective in elongation of median survival time. Combination of ACNU, methotrexate and OK-432, in the same schedule as described above, produced the longest median survival time of 42.4%, statistically significant (P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Glioma; Injections, Intraperitoneal; Meningeal Neoplasms; Methotrexate; Neoplasm Transplantation; Nimustine; Nitrosourea Compounds; Picibanil; Rats; Rats, Inbred Strains

Topics: Astrocytoma; Biological Products; Brain Neoplasms; Combined Modality Therapy; Drug Therapy, Combination; Ependymoma; Fluorouracil; Glioma; Humans; Lymphoma; Meningeal Neoplasms; Meningioma; Nimustine; Nitrosourea Compounds; Oligodendroglioma; Picibanil

Topics: Animals; Body Weight; Brain Neoplasms; Carboxymethylcellulose Sodium; Dose-Response Relationship, Drug; Interferons; Male; Methylcellulose; Neoplasm Transplantation; Nimustine; Nitrosourea Compounds; Peptides; Picibanil; Poly I-C; Polylysine; Rats

Topics: Adjuvants, Immunologic; Adult; Antineoplastic Agents; Brain Neoplasms; Dacarbazine; Drug Therapy, Combination; Female; Humans; Male; Melanoma; Nimustine; Nitrosourea Compounds; Picibanil; Skin Neoplasms; Vincristine

Penicillin-free-Picibanil was injected into the brain of Wistar/Fibiger strain rat to investigate the histological changes. Its effect on the growth of rat schwannoma inoculated in the brain was also examined histologically. Picibanil caused the most prominent but focal lymphoreticular cell reaction around the injected site in the brain 24 to 48 hours after injection. The cells infiltrating from the blood vessels were neutrophils, monocytes, lymphocyte-like cells, histiocyte-like cells and unidentified cells. This lympho-reticular cell reaction gradually subsided in the next 4 to 5 days. Neutrophils and monocytes (macrophages)stayed till the later phase. Two weeks later, the lesion was minimal with only mild glial changes. Picibanil was however, considered to exert at the site of injection neurotoxic and glia-toxic activity at a concentration of 0.1 KE/10 microliters. The rat schwannoma (T1) cells, when inoculated without any treatment, showed vivid growth in the brain and no lympho-reticular cell reaction was observed. When the T1 tumor cells, suspended in the Picibanil solution, were inoculated into the brain, no lymph-reticular cell reaction was observed 7 and 14 days after inoculation. However, when the rat was pretreated with Picibanil into the brain 7 days before inoculation, only a mild lymphoreticular cell reaction was observed around the T1 cells till 7 days after inoculation. Accordingly, Picibanil was considered to induce nonspecific immunological in the rat brain even around the glioma.

Topics: Animals; Biological Products; Brain Neoplasms; Female; Injections, Intraventricular; Male; Neoplasms, Experimental; Neurilemmoma; Picibanil; Rats

Topics: Adult; Aged; Brain Neoplasms; Child; Female; Glioma; Humans; Immunity, Cellular; Immunotherapy; Male; Middle Aged; Phytohemagglutinins; Picibanil; Tuberculin Test

Topics: Antineoplastic Agents; Brain Neoplasms; Doxorubicin; Drug Therapy, Combination; Glioma; Humans; Picibanil; Semustine

Thirteen patients with malignant brain tumors, 12 anaplastic gliomas and one metastatic tumor, received repeated intratumoral injections of an immunopotentiator, Picibanil, prepared from streptococcus pyogenes. All patients tolerated this therapy; morbidity rates were acceptable. Significant tumor regression was noted on computerized tomography scanning for 6 of 12 patients for whom scanning was performed. Histologic examination of the post-therapy specimens obtained from 8 patients revealed that inflammatory reactions were evoked in all of the tumors, although the extent of inflammatory changes varied from patient to patient and mostly was localized to an area surrounding the intratumoral tubes.

Topics: Adjuvants, Immunologic; Adult; Aged; Biological Products; Brain Neoplasms; Female; Glioma; Humans; Injections; Male; Middle Aged; Neoplasm Metastasis; Picibanil; Streptococcus pyogenes; Tomography, X-Ray Computed